Researchers from Julia Mahamid’s EMBL Heidelberg research group published two papers in the journal Cell detailing how cryo-electron tomography (cryo-ET) maps complex molecular interactions inside flash-frozen bacterial cells. By visualizing protein production and transport machinery in 3D, the findings reveal how cellular processes are physically coordinated across living communities.
Mapping the Cellular Cityscape with Cryo-ET
Biologists have long conceptualized cells as bustling urban environments complete with factories, power grids, and logistics networks. Historically, however, isolating individual components stripped away the context of how these systems communicate and operate in tandem. Cryo-ET changes that computational and structural paradigm.
This advanced imaging technique permits scientists to peer deep inside flash-frozen cells in three-dimensional detail, capturing molecular machines in their native environments. Rather than observing a single isolated protein species, researchers can now track active functional states across hundreds of individual cells.
“Both projects are essentially proofs of concept for this kind of analysis,” explained Joe Dobbs, lead author on one of the papers and a former PhD fellow in Mahamid’s group, currently a postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt. “Rather than looking at a single type of molecule in isolation, both papers examine interactions between different cellular systems with a common thread of understanding how different processes are coordinated.”
Connecting Transcription and Translation in Mycoplasma pneumoniae
Dobbs and his colleagues focused their high-resolution imaging efforts on Mycoplasma pneumoniae bacteria. By reconstructing detailed cellular maps, the team counted and localized instances of ribosomes—the cell’s primary protein-production machinery—across various functional states.
The imaging revealed several novel complexes directly binding transcription (the synthesis of mRNA from DNA) with translation (the creation of proteins). This structural evidence supports long-hypothesized ‘supercomplexes’ that tightly regulate gene expression. Researchers identified ribosomal subunits attached to the cell membrane even during non-productive phases, indicating that these subunits may only detach when conditions trigger a fresh round of protein manufacturing. This conservation of mechanical behavior mirrors observations made decades ago in mammalian cells, hinting at deeply rooted evolutionary mechanisms.
As Dobbs described the dynamic ecosystem: “The molecular machines I work on are like little factories that produce things, while some of my colleagues have been studying systems that transport and process those products. Together, they form different parts of a living molecular community inside the cell – much like a city with different specialized activities all working together.”
Uncovering New Protein Transport Machinery at the Cell Border
Addressing the cellular logistics pipeline from a different angle, Rasmus Jensen led an investigation within the Mahamid group into protein transportation and folding at the cellular membrane.
“Joe started with a biological question he wanted to answer,” Jensen noted. “I started from the opposite direction. We’d seen something interesting in the cell and worked backwards to figure out what it was, eventually discovering that it’s a new configuration of a molecular machine that helps proteins either be exported out of the cell or inserted into its membrane.”
By blending cryo-ET imaging, proteomics, and computational protein structure predictions, the research team isolated a novel configuration featuring the well-known Sec-translocon—a membrane channel that exports newly synthesized proteins—alongside three previously unknown helper proteins. These auxiliary proteins assist in folding transported cargo into functional shapes immediately outside the cell membrane.
The resulting structural data provide the most detailed images so far of how bacterial protein transport physically interfaces with extracellular folding systems.
